Hepatitis: Tokyo

Miyamura T. · National Institute of Infectious Diseases, 1-23-1 Toyama Shinjuku-ku, Tokyo 162-8640, Japan. · Adv Drug Deliv Rev. · Pubmed #17889399 No free full text.

This publication has no abstract.

Miyakawa Y, Yoshizawa H. · Miyakawa Memorial Research Foundation, Minami-Aoyama 2-19-8, Minato-Ku, Tokyo 107-0062, Japan. · Hepatol Res. · Pubmed #17092770 No free full text.

This publication has no abstract.

Kurosaki M, Izumi N. · Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan. · Hepatol Res. · Pubmed #16303326 No free full text.

This publication has no abstract.

Hirata Y, Sudoh M, Kohara M. · Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. · Uirusu. · Pubmed #19374199 links to  free full text

Abstract: Hepatitis C virus (HCV) develops persistent infection in most infected patients, and eventually cause chronic hepatitis, liver cirrhosis and then hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves the efficacy in many patients, while it does not lead to sufficient achievements in genotype1b patients. To invent new anti-HCV reagent, we focused on host factors which HCV take advantage of in its life-cycle. We identified serine palmitoyltransferase inhibitor as anti-HCV reagent through high-through put screenig using HCV replicon cells. Moreover, we evaluate the anti-HCV effect of SPT-inhibitor in vivo with humanized chimeric mice. SPT-inhibitor led to rapid decline in serum HCV-RNA of about 1-2log within 8 day, futhermore the combination therapy of SPT-inhibitor and PEG-IFN achieved about 3log reduction in serum HCV-RNA. At last, we investigated the mechanism of anti-HCV effect of SPT-inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft, in which the replication of HCV occur. We investigated the influence of SPT-inhibitor to lipid rafts by analysing the detergent resistant membrane (DRM). The analysis proved that SPT inhibitor got HCV RNA dependent RNA polymerase (NS5B) to move to detergent soluble fraction from DRM, and Biacore analysis indicated the binding of sphingomyelin to NS5B. These results suggested SPT inhibitor got NS5B to release from replication complex.

Suzuki T, Masaki T, Aizaki H. · National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo. · Uirusu. · Pubmed #19374198 links to  free full text

Abstract: A robust system for production of recombinant infectious hepatitis C virus (HCV) has been established in 2005 and classical virological techniques are now able to be applied to the HCV research, especially regarding molecular mechanisms on virion assembly and maturation. We recently demonstrated that the C-terminal serine cluster of NS5A is a determinant of NS5A interaction with Core and the subcellular localization of NSSA. Mutation of this cluster blocks the NS5A-Core interaction, resulting in perturbation of association between Core and HCV RNA. It is thus tempting to consider that NS5A plays a key role in transporting the viral genome RNA synthesized by the replication complex to the surface of lipid droplets (LDs) or LD-associated membranes, where Core localizes, leading to facilitation of nucleocapsid formation. We also demonstrated an important role of cholesterol and sphingolipid in HCV infection and virion maturation. Specifically, mature HCV particles are rich in cholesterol. Depletion of cholesterol from HCV or hydrolysis of virion-associated sphingomyelin results in a loss of infectivity, and the addition of exogenous cholesterol restores infectivity. In addition, cholesterol and sphingolipid on the HCV membrane play a key role in virus internalization. Finally, inhibitors of the sphingolipid biosynthetic pathway efficiently block virion production.

Koike K. · Department of Infectious Diseases, University of Tokyo, Japan. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #19346715 No free full text.

This publication has no abstract.

Masuzaki R, Yoshida H, Tateishi R, Shiina S, Omata M. · Department of Gastroenterology, University of Tokyo, Bunkyo-ku, Tokyo, Japan. · Best Pract Res Clin Gastroenterol. · Pubmed #19187872 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and its incidence is increasing in the United States and elsewhere. The prognosis of HCC patients depends not only on tumour stage but also on the background liver function reservoir. Current options for the treatment of HCC are surgical resection, liver transplantation, transcatheter arterial embolization, chemotherapy, and percutaneous ablation therapy. The choice of optimal treatment for individual patients, especially those at an earlier cancer stage, is sometimes controversial. Short-term prognosis of HCC patients has been much improved recently due to advances in early diagnosis and treatment, although long-term prognosis is as yet far from satisfactory as indicated by the overall survival at 10 years after apparently curative treatment of only 22-35%. Prevention of HCC recurrence, or tertiary prevention, is one of the most challenging tasks in current hepatology.

Usui M, Minoda H. · Department of Ophthalmology, Tokyo Medical University. · Nippon Rinsho. · Pubmed #19177759 No free full text.

Abstract: In this paper, we review sexually transmitted diseases (STD) involving the eye. Recently conjunctivitis due to Chlamydia trachomatis in children and adults is increasing, and that of Neisseria gonorrhoeae resistant to multiple antibiotics has attracted special attention in our country. Syphilis has many ocular manifestations such as keratitis, iridocyclitis, retinochorioiditis, and neuritis, etc. Ocular complications related to HIV infection, including HIV retinopathy, cytomegalovirus retinitis, zoster ophthalmics, and Kaposi s sarcoma in conjunctiva are increasing in Japan. Phthirus pubis infection of the eye lid, and human T-cell lymphotropic virus type 1 (HTLV-1)-associated uveitis are occasionally reported. Furthermore conjunctival tumor associated with human papilloma virus (HPV) infection, acute retinal necrosis(ARN) due to herpes simplex virus type 2 (HSV-2), as well as hepatitis B virus (HVB) and hepatitis C virus (HVC) retinopathy are also mentioned in this review.

Suzuki F. · Department of Hepatology, Toranomon Hospital, Tokyo 105-8470, Japan. · Rinsho Byori. · Pubmed #19086457 No free full text.

Abstract: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major viruses known to cause viral hepatitis. Serological markers are commonly used as diagnostic and/or prognostic indicators of acute or chronic HBV or HCV infection. The ability to detect HBV DNA in serum has been reported to have prognostic value for the outcome of chronic HBV infection. A rapid and sustained drop in HBV DNA or HCV RNA levels in patients under therapy has been shown to be a predictive factor for a favourable treatment outcome. Various techniques for detecting HBV DNA or HCV RNA have already been described; however, there are various problems with the sensitivity or detection range of those methods. New virus measuring methods have recently been reported and used. The Cobas Taq Man HCV Test is a new method to detect HBV DNA and HCV RNA with higher sensitivity and a broader range of quantitation than conventional methods. Some reports have shown that these methods improve therapy monitoring and the management of HBV or HCV infection. Moreover, hepatitis E virus (HEV) infection has been reported in Japan. The clinical features and viral markers of HEV have also been described.

Kimura T, Noguchi Y, Shikata N, Takahashi M. · Quality Assurance and External Scientific Affairs Department, Ajinomoto Co., Inc, Tokyo, Japan. · Curr Opin Clin Nutr Metab Care. · Pubmed #19057187 No free full text.

Abstract: PURPOSE OF REVIEW: To highlight the usefulness of amino acid profiling in clinical diagnosis and current developments in analysis revealing underlying metabolic relationships. RECENT FINDINGS: Recent innovations in metabolomics and systems biology enable high throughput measurement of diverse amino acids and the subsequent data mining for various uses. Recent studies show new possibilities of using plasma amino acid analysis as biomarker discovery tools by generating diagnostic indices through systematic computation. Such studies show that amino acid-based clinical diagnostic indices for hepatic fibrosis in type C hepatitis patients can be generated. In addition, several studies show the potential of treating amino acid profile data as a metabolomic subset, which can be integrated through the analysis of correlation with different types of 'omics' data for describing metabolite-to-metabolite or metabolite-to-gene interaction networks. CONCLUSION: Amino acid profiling of biological samples could be used to generate indices that could be used for clinical diagnosis and is a useful tool for understanding metabolic implications under various physiological conditions. Although further improvements in analytical methods are needed, amino acids could be useful indicators for facilitating nutritional management of specific physiological and pathological states.

Otsubo H, Yamaguchi K. · Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan. · Jpn J Infect Dis. · Pubmed #19050347 links to  free full text

Abstract: Over the past decades, the incidence of transfusion-transmitted diseases has been dramatically reduced. These reductions have been due to a multifocal approach to the collection, processing, and release of blood components. The estimated risks of transfusion-transmitted hepatitis viruses are now extremely small, but the possibility of infections with emerging pathogens always exists because preventive measures may not be available for all cases. Thus, some patients may be harmed before preventive measures are introduced. Beside transfusion-transmitted infections (TTI), unsolved residual risks such as transfusion-related acute lung injury or incompatible blood components transfusion still exist as major concerns. Continuous efforts toward research on and the prevention of adverse reaction-related blood components must be made to ensure blood safety. The purpose of this article is to introduce the concept of the current risks of transfusion including TTI, review the preventive measures already implemented, and discuss future visions for transfusion safety in Japan.

Nagai H, Sumino Y. · Division of Gastroenterology and Hepatology, Toho University Medical Center, Omori Hospital, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan. · Recent Pat Anticancer Drug Discov. · Pubmed #18991790 No free full text.

Abstract: The majority of primary liver cancer is hepatocellular carcinoma (HCC). HCC has increased in many countries, particularly where hepatitis C virus infection is more common than hepatitis B virus infection. Several non-surgical treatment options, including transcatheter arterial embolization, percutaneous ethanol injection, microwave coagulation, and radiofrequency ablation have been developed and are widely used for unresectable HCC. However, these modalities are not indicated for patients with multifocal disease, invasion or thrombosis of major blood vessels, and poor liver function. The majority of patients with advanced hepatocellular carcinoma (aHCC) do not survive for longer than 6 months from the time of diagnosis. Combined intra-arterial chemotherapy is one of the few remaining options for patients with aHCC. Continuous local arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP) via an infuser pump and implanted reservoir has been shown to prolong the survival of patients with aHCC. When LC patients with aHCC undergo chemotherapy, we should consider the influence of both tumor factors and host immunity. This review focuses on therapeutic strategy of patients with aHCC by using combined intra-arterial chemotherapy and the influence of host immunity on the response to such chemotherapy based on our results. The present article shows some recent patents related to the field.

Hiroishi K, Ito T, Imawari M. · Department of Gastroenterology, Showa University School of Medicine, Tokyo, Japan. · J Gastroenterol Hepatol. · Pubmed #18761560 No free full text.

Abstract: Immune responses against hepatitis C virus (HCV) play a crucial role in the pathogenesis of chronic hepatitis C. HCV infection often persists and leads to chronic hepatitis and eventually cirrhosis. Accumulated data suggest that HCV proteins suppress host immune responses through the suppression of functions of immune cells, such as cytotoxic T lymphocytes, natural killer cells, and dendritic cells. They also suppress the type 1 interferon signaling system. The resulting insufficient immune responses against HCV lead to the sustained infection. The appropriate control of immune responses would contribute to the eradication of HCV and the improvement of hepatitis, but there are still many issues to be clarified. This review describes the scientific evidence to support these emerging concepts, and will touch on the implications for improving antiviral therapy.

Nakamura M, Saito H, Hibi T. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. · Keio J Med. · Pubmed #18677087 links to  free full text

Abstract: The research for hepatitis C virus (HCV) has long delayed by missing of in vitro culture system. Since the development of replicon system, a replication system of subgenomic HCV RNAs in a hepatoma cell line, has been reported, many virological and clinical findings have been discovered. Recently, in addition of subgenomic replication system, hepatitis C virus full-length RNA replication has been possible, and a few cell culture systems producing viral particles have been produced. These developments enabled us to investigate the life cycle or intracellular circumstance of HCV production. By screening of newly synthesized drugs with this replicon system, several possible medicines have been established and clinical researches are now running. Among them, VX950 and SCH503034 are nearest to clinical use. Other possible agents for reducing viral replication such as cyclophyllin inhibitors, inhibitors of sphingomyelin synthesis, HMG-CoA reductase inhibitors, or RNA-dependent RNA polymerase inhibitors have been also investigated. Furthermore the mechanism for development of hepatocellular carcinoma in the HCV infected liver has been vigorously studied using the HCV replicon system.

Watanabe S, Yaginuma R, Ikejima K, Miyazaki A. · Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. · J Gastroenterol. · Pubmed #18648737 No free full text.

Abstract: Emerging attention has been paid to metabolic syndrome, which comprises several metabolic disorders including visceral obesity, diabetes mellitus, dyslipidemia, and hypertension. Whether the severity of each disease is mild to moderate, the comorbidity of these metabolic disorders has a serious impact on the development of atherosclerosis. Nonalcoholic fatty liver disease (NAFLD) is the major hepatic disorder in patients with metabolic syndrome, and indeed it is the most common cause of abnormal liver function tests in the working population in industrialized countries. In recent years, it has become recognized that NAFLD is no longer just a trivial disease, and a rather considerable proportion of the patients develop liver cirrhosis. Furthermore, chronic infection of hepatitis C virus also develops a pathological feature of steatohepatitis, and extended hepatic steatosis has a serious impact not only on the progression of hepatic fibrosis but also on the antiviral efficacy of interferon therapy. Emerging lines of studies indicated that insulin resistance, abnormal lipid metabolism, and dysregulation of cytokines/adipokines (e.g., tumor necrosis factor-alpha, adiponectin, and leptin) are profoundly involved in the pathogenesis of NAFLD. This review aims to integrate the reported evidence and to provide the current point of view for comprehensive understanding of the pathophysiology of steatohepatitis.

Sakamoto M, Mori T, Masugi Y, Effendi K, Rie I, Du W. · Department of Pathology, Keio University School of Medicine, Tokyo, Japan. · Intervirology. · Pubmed #18544947 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. HCC occurs mainly in chronically diseased livers, e.g. following hepatitis B and C infection. These high-risk patients are closely followed up, and increasing numbers of small equivocal lesions are detected by imaging diagnosis. They are now widely recognized as precursor or early-stage HCCs and are classified as dysplastic nodule or early HCC. These lesions lack typical imaging and histology of ordinary HCC and do not show elevated serum markers of alpha-fetoprotein and PIVKA-II, for example. Molecular analysis of these lesions would help to develop molecular markers for objective histological diagnosis of early HCC and possibly new serum markers for early detection of HCC. It has been reported that HSP70, CAP2, glypican 3 and glutamine synthetase could serve as molecular markers for early HCC. Further analysis is expected to evaluate their usefulness in routine pathological diagnosis including biopsy diagnosis and also as serum markers for early detection of HCC.

Ichida K. · Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences. · Nippon Rinsho. · Pubmed #18409528 No free full text.

Abstract: An inhibitor of xanthine dehydrogenase (XDH), allopurinol, and uricosuric agents, probenecid and benzbromarone, have been used for more than 20 years in the treatment of hyperuricemia and gout. However, they are inconvenient in some situations. With regard to allopurinol, the dosage reduction is recommended in patients with renal insufficiency for preventing from rare adverse effect, bone marrow depression. Benzbromarone also has quite rare adverse effect, fulminant hepatitis. Recently several new therapies have been developed such as new XDH inhibitors urate transporter (URAT) 1 inhibitor, and a modified recombinant uricase. The dosage reduction of the new XDH inhibitors, febuxostat and FYX-051, is not necessary in patients with renal insufficiency because renal excretion is not main excretory pathway. JTT-552 is a first medicine targeting on URAT1. Polyethylene glycol (PEG) conjugation with recombinant uricase sufficiently reduces the immunogenicity to permit repeated dosing and the clinical trials are ongoing for patients with treatment-failure gout and hyperuricemia.

Yotsuyanagi H, Koike K. · Department of Infection Control and Prevention, Division of Microbiology Graduate School of Medicine and Faculty of Medicine, University of Tokyo. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #18250590 No free full text.

This publication has no abstract.

Yasunaga H. · Department of Planning, Information and Management, University of Tokyo Hospital, Tokyo, Japan. · Lancet. · Pubmed #18083405 No free full text.

Abstract: In 1977, the US Food and Drug Administration revoked all licences for fibrinogen concentrate because of the risk for hepatitis infection and suspected lack of effectiveness. However, in Japan, fibrinogen concentrate was used routinely for treatment of obstetric bleeding until 1988. Even in 1997, academic texts by Japanese authorities in obstetrics still recommended that obstetricians use the product. An estimated 10 000 cases of hepatitis C infection are attributable to use of fibrinogen in Japan and are a result of authoritarianism that hindered effective policy changes. Scientists have a duty to refine repeatedly the quality of their evidence, and policymakers need to adjust existing policies continually to accord with the latest scientific evidence.

Kanai Y, Hirohashi S. · Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. · Carcinogenesis. · Pubmed #17893234 links to  free full text

Abstract: Alterations of DNA methylation are one of the most consistent epigenetic changes in human cancers. Human cancers generally show global DNA hypomethylation accompanied by region-specific hypermethylation. Alterations of DNA methylation may result in chromosomal instability as a result of changes in chromatin structure. DNA hypermethylation of CpG islands silences various tumor-related genes. Alterations of DNA methylation are frequently observed in cancers associated with chronic inflammation and/or persistent infection with viruses or other pathogenic microorganisms, such as hepatitis B or C viruses, Epstein-Barr virus, human papillomavirus and Helicobacter pylori, or with cigarette smoking. Accumulating evidence suggests that alterations of DNA methylation are involved even in the early and precancerous stages. On the other hand, in patients with cancers, aberrant DNA methylation is significantly associated with poorer tumor differentiation, tumor aggressiveness and poor prognosis. Precancerous conditions showing alterations of DNA methylation may progress rapidly and generate more malignant cancers. DNA methyltransferase (DNMT) 1 over-expression is not a secondary result of increased cell proliferative activity but is significantly correlated with the CpG island methylator phenotype, which is defined as frequent DNA hypermethylation of C-type CpG islands that are usually methylated in a cancer-specific (not age-dependent) manner. Splicing alteration of DNMT3b may result in chromosomal instability through DNA hypomethylation of pericentromeric satellite regions. Alteration of DNA methylation may become an indicator for carcinogenetic risk estimation and early diagnosis of cancers and a biological predictor of poor prognosis in patients with cancers. Correction of DNA methylation status may offer a new strategy for prevention and therapy of cancers.

Suzuki T, Ishii K, Aizaki H, Wakita T. · Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. · Adv Drug Deliv Rev. · Pubmed #17825945 No free full text.

Abstract: Hepatitis C virus (HCV) has been recognized as a major cause of chronic liver diseases worldwide. Molecular studies of the virus became possible with the successful cloning of its genome in 1989. Although much work remains to be done regarding early and late stages of the HCV life cycle, significant progress has been made with respect to the molecular biology of HCV, especially the viral protein processing and the genome replication. This review summarizes our current understanding of genomic organization of HCV, features of the viral protein characteristics, and the viral life cycle.

Watanabe T, Umehara T, Kohara M. · Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. · Adv Drug Deliv Rev. · Pubmed #17822803 No free full text.

Abstract: RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing by double-stranded RNA. Because the phenomenon is conserved and ubiquitous in mammalian cells, RNAi has considerable therapeutic potential for human pathogenic gene products. Recent studies have demonstrated the clinical potential of logically designed small interfering RNA (siRNA). However, there are still obstacles in using RNAi as an antiviral therapy, particularly for hepatitis C virus (HCV) that displays a high rate of mutation. Furthermore, delivery is also an important obstacle for siRNA based gene therapy. This paper presents the potential applications and the hurdles facing anti-HCV siRNA drugs. The present review provides insight into the feasible therapeutic strategies of siRNA technology, and its potential for silencing genes associated with HCV disease.

Takemura N, Sugawara Y, Tamura S, Makuuchi M. · Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · Dig Dis Sci. · Pubmed #17805972 No free full text.

Abstract: Hepatitis B surface antigen-negative and hepatitis B core antibody-positive grafts were considered unsuitable for transplantation. The number of potential recipients for liver transplantation now exceeds that of potential donor organs, which has led us to reevaluate the feasibility of these grafts. Several strategies involving prophylactic administration of hepatitis B immunoglobulin and/or lamivudine to transplant recipients have been proposed. At the University of Tokyo, we have continued to use hepatitis B immunoglobulin monoprophylaxis with zero recurrence.In this article we report our experience with the use of hepatitis B surface antigen-negative/hepatitis B core antibody-positive grafts with hepatitis B immunoglobulin monotherapy. We conducted a review of the literature regarding the feasibility of these grafts to reconfirm optimal prophylactic strategies for preventing de novo hepatitis B virus infection in transplant recipients.

Suzuki T, Aizaki H, Murakami K, Shoji I, Wakita T. · Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Tokyo, Japan. · J Gastroenterol. · Pubmed #17671755 No free full text.

Abstract: Infection with hepatitis C virus (HCV), which is distributed worldwide, often becomes persistent, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma. For many years, the characterization of the HCV genome and its products has been done by heterologous expression systems because of the lack of a productive cell culture system. The development of the HCV replicon system is a highlight of HCV research and has allowed examination of the viral RNA replication in cell culture. Recently, a robust system for production of recombinant infectious HCV has been established, and classical virological techniques are now able to be applied to HCV. This development of reverse genetics-based experimental tools in HCV research can bring a greater understanding of the viral life cycle and pathogenesis of HCV-induced diseases. This review summarizes the current knowledge of cell culture systems for HCV research and recent advances in the investigation of the molecular virology of HCV.

Koike K. · Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan. · J Gastroenterol Hepatol. · Pubmed #17567457 No free full text.

Abstract: Persistent infection with hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC). However, it remains controversial in the pathogenesis of HCC associated with HCV as to whether the virus plays a direct or an indirect role. The studies using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation would also play a role. The downstream events of the core protein are segregated into two components. One is the augmented production of oxidative stress along with the activation of scavenging system, including catalase and glutathione, in the putative pre-neoplastic stage with steatosis in the liver. Thus, oxidative stress production in the absence of inflammation by the core protein would partly contribute to the development of HCC. The generation of oxidative stress is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other component is the alteration of intracellular signaling cascade of mitogen-activated protein kinase and activating factor (AP)-1, leading to the activation of cell cycle control. The combination of these pathways, collective with HCV-associated alterations in lipid and glucose metabolism, would lead to the frequent development of HCC in persistent HCV infection. These results suggest that there would be a mechanism for hepatocarcinogenesis in persistent HCV infection that is distinct from those for the other cancers. Similar to the pathogenesis of other cancers, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore unlike for other cancers, HCV infection may be able to cause HCC in the absence of a complete set of genetic aberrations. Such a scenario, 'non-Vogelstein-type' carcinogenesis, would explain the rare feature of hepatocarcinogenesis in HCV infection, the extraordinarily high incidence and the multicentric nature of HCC development.